The angiogenic inhibitor long pentraxin PTX3 forms an asymmetric octamer with two binding sites for FGF2

Antonio Inforzato, Clair Baldock, Thomas A. Jowitt, David F. Holmes, Ragnar Lindstedt, Marcella Marcellini, Vincenzo Rivieccio, David C. Briggs, Karl E. Kadler, Antonio Verdoliva, Barbara Bottazzi, Alberto Mantovani, Giovanni Salvatori, Anthony J. Day

Research output: Contribution to journalArticle

Abstract

The inflammation-associated long pentraxin PTX3 plays key roles in innate immunity, female fertility, and vascular biology (e.g. it inhibits FGF2 (fibroblast growth factor 2)-mediated angiogenesis). PTX3 is composed of multiple protomers, each composed of distinct N- and C-terminal domains; however, it is not known how these are organized or contribute to its functional properties. Here, biophysical analyses reveal that PTX3 is composed of eight identical protomers, associated through disulfide bonds, forming an elongated and asymmetric, molecule with two differently sized domains interconnected by a stalk. The N-terminal region of the protomer provides the main structural determinant underlying this quaternary organization, supporting formation of a disulfide-linked tetramer and a dimer of dimers (a non-covalent tetramer), giving rise to the asymmetry of the molecule. Furthermore, the PTX3 octamer is shown to contain two FGF2 binding sites, where it is the tetramers that act as the functional units in ligand recognition. Thus, these studies provide a unifying model of the PTX3 oligomer, explaining both its quaternary organization and how this is required for its antiangiogenic function.

Original languageEnglish
Pages (from-to)17681-17692
Number of pages12
JournalJournal of Biological Chemistry
Volume285
Issue number23
DOIs
Publication statusPublished - Jun 4 2010

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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    Inforzato, A., Baldock, C., Jowitt, T. A., Holmes, D. F., Lindstedt, R., Marcellini, M., Rivieccio, V., Briggs, D. C., Kadler, K. E., Verdoliva, A., Bottazzi, B., Mantovani, A., Salvatori, G., & Day, A. J. (2010). The angiogenic inhibitor long pentraxin PTX3 forms an asymmetric octamer with two binding sites for FGF2. Journal of Biological Chemistry, 285(23), 17681-17692. https://doi.org/10.1074/jbc.M109.085639